211 replies to this topic

[John Schloendorn]

John and prometheus, what is your educated guess as to the benefits/consequences of mimicking the silencing if SIRt1/2 in humans?

I don't have an educated guess, really. If you're interested in my blind guess though it would be no strong effect on life-span, perhaps increased vulnerability to certain stressors, perhaps slightly more cancer. I would not expect any modulation of a single endogenous gene to have a strong life-extending effect, but it is really not productive to speculate about that, since the necessary experiments are utterly impracticable for the usual reasons (lack of a technology to do it, death of the experimenter from aging before a result is obtained).

[jays]

For the silencing of the Sir2/Sirt1 genes in particular couldn’t we have a response proportional to the life span of the animal rather than inversely proportional, since these genes actually regulate the DNA repair in the organism? And maybe each category of genes is a different case? Probably the very fact that the genes regulate these mechanisms indicates that anti-aging efforts of the organism can be modulated to an increased efficiency. Anyways nothing that experiment won’t answer.

[Karomesis]

Suppose tommorow we succeeded in producing a complex nanobot, what are the limitations of such a machine? could we theoretically fix our cells and overcome pathologies very rapidly? i.e. freitas and other pioneers envisionings.

[John Schloendorn]

Suppose tommorow we succeeded in producing a complex nanobot, what are the limitations of such a machine?

I have no idea what you are asking. If Freitas imagines there might be a machine that can repair cells, and we design and create Freitas' machine, then yes it can repair cells... There is no information in that statement. Are you asking if we think that Freitas et al's proposals are realistic, i.e. such machines can be designed and created?

[Karomesis]

John, I am asking what the theoretical limitations are of a nanobot, As in, what would you do with a nanobot capable of manipulating cells to quickly overcome the "blight of involuntary death"? And how rapidly could it be accomplished? I have little doubt as to the possibilities of such a machine, rather, I seek a bioperspective on its implications. Are there unheard of obstacles in biology that prohibit such a contraption from fixing biological problems? before, it was assumed that crosslinks were unbreakable, we now know this to be false, how many more assumptions are incorrect?

[John Schloendorn]

how many more assumptions are incorrect?

Perhaps all those that contain an "impossible"... I do know any reason to believe that arbitrarily hard medical problems cannot be solved with arbitrarily sophisticated medical technology. Is that what you mean?

[John Schloendorn]

what would you do with a nanobot capable of manipulating cells to quickly overcome the "blight of involuntary death"?

Publish everything about it, drop on a sunny beach in a far-off threshold country and see what happens.

[john e]

What simple methods are available or in research that would help us to discharge impurities from our body?

Example:
I had a sist removed from my left ear. I have had troubles with heartburn and learned that sleeping on the left side caused probleme with heartburn. Now that I'm sleeping on my right side most of the time, I am getting wax build-up in my right ear but not in my left. Yeah, that makes sense now. Using solutions to clean the wax is to much of a hassle and I don't think it's good for the eardrum to be exposed to "cleaning solutions". I am currently using cotton swabs sticks very carefully to clean the right ear out with. I'm wondering if ther are better "tools" to clean out our ears from the impurities that are trying to escape from our body.
~John

[liorrh]

how far are we from gene therapy? how will it work? for instance I read a research on regrowing cartilage in a mouse's knee, curing osteoarthritis. why isn't it going to use for humans as well.

Edited by liorrh, 16 December 2005 - 01:14 AM.

[Cyto]

how far are we from gene therapy?

I am not one to give dates, maybe someone more willing to do that can? But let me put most of my answer in your next question...

how will it work?

One method that I am a fan of being the "next big thing" are SSRs or Site Specific Recombinases. These come in a variety from bacteriophages, those little "viruses of the bacterial world." These have been mutated to allow for compatibility with integrating into mammalian genomes - keep in mind though that this still isn't perfected - but there was a recent murine model that gave good results (http://www.pnas.org/...ct/102/43/15581). The recombinases work in groups with one-another in the process shown down below in the Figure, they will exploit the use of tyrosine's side chain which can link with the phosphate of DNA sequence - allowing for it to pull the strand to a closer proximity with another strand. A key advantage that these have is 25-30 (and Im also reading 30-50) nucleotide specificity when targeting where to integrate something. When virions like HIV are still having multiple factors found for how it can integrate (http://www.nature.co...abs/nm1329.html) and a lot less specificity then we need to turn to a more fidelic tool. The same goes for adenovirions as well even through they are in common use, unlike HIV. In this case I would see humans being more inclined to use something with high targeting over something we would still feel iffy about. And this is one way that I view us having more freedom to choose what we want, rather than just know that "it will integrate at a region where there is high transcription."

An idealistic point would be having mammalian artificial chromosomes (MACs) in which we have sites, which have been constructed for integration purposes with a desired gene or genes. I do think SSRs are the step into this reality though.

for instance I read a research on regrowing cartilage in a mouse's knee, curing osteoarthritis. why isn't it going to use for humans as well.

This sounds more like stem cell mediated therapy... Don't keep up on a lot of studies, sources would help me figure out what your talking about here.





If you need me to talk about something in more detail please do tell me.

-Bates

Edited by Bates, 16 December 2005 - 04:22 AM.

[liorrh]

I didn't find the specific one that I read but here are some I want explained, I mean when this will be available to me :-)
as far as I can tell its all gene therapy and not stemcell research, but you tell me.

http://www.ncbi.nlm....3400&query_hl=9

http://www.ncbi.nlm....8043&query_hl=1

http://www.ncbi.nlm....9641&query_hl=1

http://www.ncbi.nlm....3281&query_hl=6

[Cyto]

Ahhh, ok.

One is...(Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints)

Exploiting the expression of Insulin Like Growth Factor I (one) (IGF-I). IGF-I is used in the proliferation of many cell-types that are not from fetal origin (why its good in this case). So local injections, which I like how they stress making this cost feasible, good thing to keep in mind. Used rabbits and adenoviral vectors for an expression of IGF-I and encouraging cell proliferation.

This increased proteoglycan production (help replace lost cartilage) which, even though it occurred, didn't seem to impact breakdown. Now this could be due to the researcher-induced antigen-induced arthritis (AIA) - which could be eliciting more agressive breakdown...I kinda doubt it though. But they did show their vector will cause a desired secretion...so it wasn't all in vain.


Another is...(Gene therapies for osteoarthritis)

Wait, this is the one talking about cost.
Anyways, interleukin-1 (IL-1) is what you can generally call a "flag" for immune response once its secreted. So knowing the problem in this case of joint inflammation drives them to target it with an antagonist (IL-1Ra) that basically can outcompete binding to the IL-1 receptor on other leukocytes (white blood cells) - this will prohibit the normal signaling. Thus they want to try this in phase-I clinicals (Is it safe? trials) but say its a cost factor prohibiting them from doing that. Too bad.


Then...(Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy)

This one takes both IGF-I and IL-1Ra and uses it in culture, keep in mind its a culture, and finds that it attains therapeutic value by day 2. Course the next thing to do with this is put it in a rabbit, mouse or something else that makes sense.


Lastly...(Retroviral transduction with SOX9 enhances re-expression of the chondrocyte phenotype in passaged osteoarthritic human articular chondrocytes)

This one was interesting. The main result showed that chondrocytes, which lay down the cartilage protein-glycan mixes, can be essentially rescued from an immune suppression of repair. They used a SOX9 protein expression vector that they say aided in priming the cells for use of IGF-I and transforming growth factor beta-3. So, SOX9 looked to act as an enhancer for the other two's actions.

[liorrh]

so... how far am I from using it on my knee, in your opinion?
(PS, I have injected straight IGF-I in my knee and it sure works, but I do not want the systemic effects of IGF-I)

[John Schloendorn]

The problem with these mouse studies is that they care most about the effect. Safety is often underreported. Health isn't monitored during the procedure, the animals aren't followed up long term, and sometimes the survival percentage is not reported.
For example, humans have died from inflammatory overreaction to adenoviral gene therapy, or from cancer as a long-term consequence of retroviral therapy (they actually found the transgene in the middle of a tumor suppressor gene in the patient's cancer cells).
Such safety issues could be monitored best in human trials, but such trials are hard to do precisely because of the safety issues. So progress is slow, and trials happen mostly for patients who have nothing to lose.

It's going to be a while.

[liorrh]

so 5-10 years?

[Karomesis]

HYpothetically, If I was a mad scientist and wanted to begin administering gene knockouts and gene therapy to people what type of equipment would I need and what would the cost be? I ask because it doesn't seem that far fetched given the fact that I can by things like a nanomanipulator from Zyvex [:o]

[John Schloendorn]

Liorrh,
At least that long. Note that this is an open-ended statement. It may never happen.

Karo,
For all that we know, you cannot successfully do it, period. Being mad doesn't change that fact.

[olaf.larsson]

Knockout-genetherapy, will most likely be siRNA knockdown therapy.

[Cyto]

Knockout or Knockdown?

One completely takes it out while the other is knocking down expression since its targeting the still active transcripts – even more since it’s a chemical system there is still going to be a small level of expression of the undesired.


----------------------------


I do agree with what John says. And I won't give timetables as well.
I can tell you that those who have passion for this science will not be simply flicking at their hair while doing this. Especially in the areas where even more work is needed, certainly selects against those lazy ones.

[demiac]

Do you know a name for the degeneration of human body, caused by aging?

[Cyto]

senescence comes to mind.

[Cyto]

Yes, sounds good.


Wiki:

In biology, senescence is the state or process of aging. For the social, cultural, and economic aspects see aging. The word senescence is derived from the Latin word senex, meaning "old man" or "old age."


Princeton, wordnet:

# aging: the organic process of growing older and showing the effects of increasing age
# agedness: the property characteristic of old age

[John Schloendorn]

Should not be confused with cellular senescence though, which is a rather defined phenotye that arrests cell division and could underlie a fraction of all "age-related pathology". The latter term is my favored answer to your question, but it's not perfect. One of its advantages is that it provokes very little opposition when you say that you want to fix it.

[demiac]

My gratitudes.

I'm looking for a word in my language, that would mean the organic process of growing old, and finnish linguistics department managed to found some corresponsive word to senescence. It was so rarely used that it wasn't really defined. Apparently this applies to several languages; people associate senescence so well with aging, that no different words are particularily needed :(

Would you happen to know an expression for aging, without physically growing older? Even better would be an expression for aging without senescence, but I dare not believe that such exists.

[DJS]

Would you happen to know an expression for aging, without physically growing older? Even better would be an expression for aging without senescence, but I dare not believe that such exists.

I believe that this thread might help. [thumb]

Superannuated, Word Contest - Narrowing The Terms

[demiac]

Sorry, superannuated is a beautiful word, but It's not a verb.

Also, I meant to ask if someone knows "expression for aging, that doesn't mean physically growing older". Sorry :I

[DJS]

Well, the reason I suggested the list is that although the words are nouns attempting to describe an "ageless" individual some of them may give you an idea for a corresponding verb.

I have one for you but it may not be "snappy" enough to fit your purposes... "negligibly senescent maturation".

[jaydfox]

Sorry, superannuated is a beautiful word, but It's not a verb.

Well, superannuated isn't a verb, but couldn't it just be a past participle of the verb superannuate?

And if you don't like superannuate, how about crescennuate? Like crescendo, from the latin crescere, to increase. Ennuate, of course, being an alternative to annuate, like from superannuate.

Edit: Added quote

Edited by jaydfox, 10 April 2006 - 01:17 PM.